Dr Marija Fjodorova

(she/her)

BA (Hons), PhD, FHEA

Publication

• Date
• Type

Research

My research focuses on how genetic risk for psychiatric and neurodevelopmental disorders disrupts the development and function of neurons in the basal ganglia. I work principally on striatal medium spiny neurons (MSNs), alongside the midbrain dopamine and cortical neurons they connect with, and on the cortico-striatal and midbrain-striatal networks they form. Research into these conditions has traditionally concentrated on the cortex, but there is growing evidence that the striatum – central to motor coordination, decision-making, reward and habit formation – is an underexplored nexus in mental health research. 

I address this through an integrated experimental approach combining in vitro differentiation of human pluripotent stem cells, contemporary genome engineering and transcriptomic analysis. My goal is to understand the molecular mechanisms of basal ganglia function and communication in health and disease, and to translate those findings into innovative therapeutic interventions.

Striatal neuron subtype imbalance in neurodevelopmental disorders

My current work asks how risk mutations for neurodevelopmental disorders disrupt striatal neuron subtype differentiation. Using human induced pluripotent stem cells carrying duplications or deletions of the 16p11.2 locus – a copy number variant conferring substantial risk for autism spectrum disorders, schizophrenia, intellectual disability and attention deficit hyperactivity disorder – I have provided the first direct evidence that these mutations cause MSN-specific developmental deficits. Duplications and deletions produce reciprocal effects on proliferation but a shared bias towards hyperresponsive direct-pathway MSNs, linking genetic risk to striatal circuit dysfunction.

This work is supported by a Royal Society Research Grant (2026), What Drives Striatal Neuron Subtype Imbalance in Neurodevelopmental Disorders? The grant funds a pooled CRISPR screen of candidate subtype regulators within the 16p11.2 locus, using CRISPR interference and activation in sister cultures read out by single-cell RNA sequencing. Positive hits are validated in CRISPR-engineered isogenic lines, and downstream signalling cascades are evaluated pharmacologically to test whether their modulation can rebalance MSN subtypes – connecting genetic changes directly to potential therapeutic strategies. Separately, seed corn funding from Cardiff University's Future Leaders in Neuroscience Research scheme supported the development of basal ganglia assembloids in my laboratory.

A role for BCL11B in medium spiny neuron homeostasis

I led the study investigating how deficiency of the BCL11B (CTIP2) transcription factor drives striatal and cortical neuron degeneration and dysfunction. Using CRISPR, I generated human embryonic stem cell lines lacking this transcription factor and characterised BCL11B-null neurons through in vitro differentiation, bulk RNA sequencing analysis, and biochemical and neuronal activity assays. This identified a striatal-specific role for BCL11B in protein kinase A-dependent protein phosphorylation and calcium signalling in response to dopamine and glutamate stimulation, with implications for schizophrenia and Huntington's disease. Collaborations with the Brain Repair Group (Cardiff University) and Inserm (Paris) confirmed similar deficits in rodent and human stem cell models of Huntington's disease. Integrating BCL11B-dependent differentially expressed genes with published genome-wide association studies, this work provided the first experimental evidence for a direct role of MSNs in schizophrenia, and suggested that the two disorders share a pathophysiology centred on the protein kinase A–calcium signalling axis.

Striatal neuron differentiation

Early in my postdoctoral career I developed an interest in using human pluripotent stem cells to generate clinically relevant neurons, extending my work into stem cell neurobiology and in vitro disease modelling in Professor Meng Li's group at the Neuroscience and Mental Health Innovation Institute, Cardiff University. My research on the induction of striatal neurons identified a role, first for Activin A and subsequently for alantolactone, within the transforming growth factor beta (TGFβ) signalling pathway in medium spiny neuron differentiation. This fully defined, TGFβ-based protocol is now recognised as one of the field's main approaches for deriving medium spiny neurons in vitro.

Collaborations

My work is supported by collaborators in developmental biology, advanced transcriptomics and psychiatric genomics, including Professor Pierre Vanderhaeghen (KU Leuven), Professor James Gusella (Massachusetts General Hospital), Professor Michael Ziller (University of Münster), and Professor James Walters and Doctor Elliott Rees at Cardiff. I am currently extending my work into neuroimmunology with Doctor Wioleta Zelek at the UK Dementia Research Institute, Cardiff.

Teaching

I am available to supervise undergraduate and postgraduate students.

Biography

2024: Hodge Lecturer in Cellular Psychiatry, School of Medicine, Cardiff University

My research vision is to understand the biological basis of mental health and neurodevelopmental disorders (NDDs), with the goal of enhancing early diagnosis and treatment. I aim to elucidate how genetic mutations increasing risk for NDDs disrupt human neuron development and function within basal ganglia circuits. My goal is to determine the extent of these contributions to disease pathogenesis and pave ways for future drug discovery.

2021 - 2023: Research Associate, School of Medicine, Cardiff University

Medical Research Council UK funded project titled “Targeting ERK signalling to ameliorate intellectual disability and autism spectrum disorder associated with chromosomal rearrangements at 16p11.2” in Professors Meng Li’s and Riccardo Brambilla’s groups.
Project outcomes:
I. Have studied striatal medium spiny neuron and cortical neuron development and function in patient-derived induced pluripotent stem cells carrying neurodevelopmental disorder-associated deletions and duplications of the 16p11.2 region. Have identified profound deficits in striatal neurogenesis and medium spiny neuron subtype imbalance in both 16p11.2 genotypes using single-cell RNA sequencing and stem cell differentiation approaches.
II. Have developed in vitro co-culture models of ‘basal ganglia’-like circuits with the aim to assess deficits in network establishment and signalling between cortico-striatal/midbrain-striatal synaptic partners in disease models.

2018 - 2021: Research Associate, School of Medicine, Cardiff University

Medical Research Council UK funded project titled “How CTIP2 deficiency drives medium spiny neuron degeneration and dysfunction” in Prof Meng Li’s Stem Cell Neurogenesis group.
Project outcomes: Discovered a role for BCL11B (aka CTIP2) in protein phosphorylation and calcium signalling in striatal medium spiny neurons with implications for schizophrenia and Huntington’s disease.

2013 - 2018: Research Associate, School of Biosciences, Cardiff University

EU 7th Framework Programme Repair-HD project in Prof Meng Li’s Stem Cell Neurogenesis group.
The main focus of this work was on the developmental biology of human neurons, specifically medium spiny neurons and dopamine neurons. The aim was to unravel molecular mechanisms behind neural fate induction and subsequent terminal differentiation via an integrated experimental approach involving in vitro stem cell differentiation and contemporary genetic manipulation. Novel strategies that drive pluripotent stem cells into clinically relevant neurons were devised and evaluated for their efficacy and functionality in vivo.
Project outcomes:
I. Generated knock-out and over-expressing human embryonic stem cell lines to study a role for BCL11B transcription factor in the development and functional maturation of striatal neurons. Revealed that BCL11B-deficient medium spiny neurons exhibit Huntington’s disease-like neuronal defects.
II. Optimised differentiation protocols for human embryonic stem cells and produced transplantable and functioning medium spiny and dopamine neurons that were successfully tested in vivo in collaboration with the Brain Repair Group at Cardiff University and Inserm in Paris.

2009 - 2013: PhD, Cardiff University

Wellcome Trust PhD in Integrative Neuroscience under the supervision of Professor Stephen Dunnett titled " Characterisation of embryonic ventral mesencephalon grafts in a rat model of Parkinson's disease". I studied striatal circuitry repair in a rat model of Parkinson’s disease and demonstrated how embryonic donor age and transplantation site affect survival and distribution of dopaminergic neurons in the grafts. This research has provided a platform for improvements to cell replacement therapy in Parkinson’s disease.

2006 - 2009: BEng (Hons) Medical Engineering (1st Class), University of Bradford

Honours and awards

2024: Fellowship of the Higher Education Academy (FHEA)

Supervisions

• Stem cell biology
• Neurobiology
• Psychiatric and neurodevelopmental disorders

Current supervision

Yuliya Tereshko

Past projects

• Olena Petter, MPhil (2025). Co-supervision with Professor Meng Li.
• Ethan Kidd, PhD (2024). Co-supervision with Professor Meng Li.